Modulation of Suppressive Activity and Proliferation of Human Regulatory T Cells by Splice-Switching Oligonucleotides Targeting FoxP3 Pre-mRNA.

Autor: Blinova VG; Laboratory of Medical Biotechnology, Institute of Biomedical Chemistry, Pogodinskaya st. 10/8, 119121 Moscow, Russia., Gladilina YA; Laboratory of Medical Biotechnology, Institute of Biomedical Chemistry, Pogodinskaya st. 10/8, 119121 Moscow, Russia., Abramova AA; Laboratory of Medical Biotechnology, Institute of Biomedical Chemistry, Pogodinskaya st. 10/8, 119121 Moscow, Russia.; Research Center of Neurology, Volokolamskoe Shosse, 80, 125367 Moscow, Russia., Eliseeva DD; Research Center of Neurology, Volokolamskoe Shosse, 80, 125367 Moscow, Russia., Vtorushina VV; National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of Ministry of Healthcare of the Russian Federation, Laboratory of Clinical Immunology, Academician Oparin st. 4, 117997 Moscow, Russia., Shishparenok AN; Laboratory of Medical Biotechnology, Institute of Biomedical Chemistry, Pogodinskaya st. 10/8, 119121 Moscow, Russia., Zhdanov DD; Laboratory of Medical Biotechnology, Institute of Biomedical Chemistry, Pogodinskaya st. 10/8, 119121 Moscow, Russia.; Department of Biochemistry, People's Friendship University of Russia Named after Patrice Lumumba (RUDN University), Miklukho-Maklaya st. 6, 117198 Moscow, Russia.
Jazyk: angličtina
Zdroj: Cells [Cells] 2023 Dec 29; Vol. 13 (1). Date of Electronic Publication: 2023 Dec 29.
DOI: 10.3390/cells13010077
Abstrakt: The maturation, development, and function of regulatory T cells (Tregs) are under the control of the crucial transcription factor Forkhead Box Protein 3 (FoxP3). Through alternative splicing, the human FoxP3 gene produces four different splice variants: a full-length variant (FL) and truncated variants with deletions of each of exons 2 (∆2 variant) or 7 (∆7 variant) or a deletion of both exons (∆2∆7 variant). Their involvement in the biology of Tregs as well as their association with autoimmune diseases remains to be clarified. The aim of this work was to induce a single FoxP3 splice variant in human Tregs by splice switching oligonucleotides and to monitor their phenotype and proliferative and suppressive activity. We demonstrated that Tregs from peripheral blood from patients with multiple sclerosis preferentially expressed truncated splice variants, while the FL variant was the major variant in healthy donors. Tregs with induced expression of truncated FoxP3 splice variants demonstrated lower suppressive activity than those expressing FL variants. Reduced suppression was associated with the decreased expression of Treg-associated suppressive surface molecules and the production of cytokines. The deletion of exons 2 and/or 7 also reduced the cell proliferation rate. The results of this study show an association between FoxP3 splice variants and Treg function and proliferation. The modulation of Treg suppressive activity by the induction of the FoxP3 FL variant can become a promising strategy for regenerative immunotherapy.
Databáze: MEDLINE
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